Regulation of Growth and Morphogenesis

Project Summary for Parent Grant, R35 GM131748 The goals of our research are to define molecular mechanisms through which mechanical forces are perceived by cells, to determine how biochemical and biomechanical signals are integrated, and to define how biochemical and biomechanical signaling networks direct formation of organs of appropriate size and shape. Our studies include investigations of intercellular signaling pathways that pattern developing organs, to define their regulation, their mechanism of action, and their transcriptional and morphogenetic outputs. We focus on the Dachsous-Fat, Hippo, and Notch signaling pathways, which are highly conserved through the animal kingdom, play multiple essential roles in the development of most organs, have been liked to congenital syndromes when inactivated, and when dysregulated can be associated with cancer. A major current focus of our research investigates links between these pathways and cells’ mechanical environment. We study how the mechanical environment, through influences on cytoskeletal tension, regulates signaling pathways, and part of our proposed research will build upon our discovery of a molecular mechanism through which tension experienced at adherens junctions influences Hippo signaling and organ growth. This mechanism is triggered by cytoskeletal tension-dependent recruitment of an Ajuba family LIM protein (Jub in Drosophila) to a-catenin at adherens junctions. Jub then recruits and inhibits the key Hippo pathway kinase, Warts, which leads to increased activity of Yorkie, a transcription factor of the Hippo pathway. This pathway is conserved in mammalian cells, and our future experiments will expand understanding of how it is regulated, and what it contributes to growth and morphogenesis in both Drosophila and mammalian models. We investigate other aspects of Hippo signaling as well, including regulation of LATS and of downstream transcription. We will also investigate a novel connection between cytoskeletal tension and Notch signaling that we have recently identified. We also investigate how signaling pathways modulate the mechanical environment to influence morphogenesis. Our planned studies will employ the Drosophila wing as a model for organ shape control, and investigate how cytoskeletal tension and the Ds-Fat signaling pathway control wing shape. These studies will employ ex vivo organ culture and image analysis to characterize cell dynamics that contribute to morphogenesis. We will also investigate feedback mechanisms that modulate tension at adherens junctions and cell behaviors through tension-dependent regulation of Ajuba family proteins and their partners. Our studies are relevant to understanding both normal development and physiology, and disease states associated with either insufficient or excess growth, or abnormal organ shape. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine.